Roche has revealed that a patient died in a phase 3 hemophilia trial of bispecific antibody emicizumab. The trial investigator ruled the death was unrelated to emicizumab, but, with the event following on from other reports of similar serious adverse reactions, it has added to questions about the safety of the experimental regimen.

Roche disclosed details of the patient death following a request from the European Haemophilia Consortium, which published the Big Pharma’s response on its website. The patient suffered two serious adverse events—a serious rectal hemorrhage followed by thrombotic microangiopathy (TMA)—before dying. Doctors treated the hemorrhage with bypassing agents, including repeated doses of activated prothrombin complex (aPCC).

The investigator concluded that the rectal hemorrhage caused the death and “that this is not related to emicizumab.” But, given that Roche has now seen several cases of TMA and two thromboembolic events in phase 3, questions remain. The events reported last year involved patients treated with Novo Nordisk’s NovoSeven or Shire’s Feiba, bypassing agents that carry thrombosis warnings, but the cause of the cases of TMA remain unclear.

Emicizumab, also known as ACE910, is tipped to be a big seller for Roche—EvaluatePharma analysts predicted it will hit $1.4 billion in annual sales in 2022 last year—but the safety concerns could scuttle its attempt to unseat incumbents such as Shire.

The phase 3 trial hit its primary endpoint of reducing bleeds over time in patients hemophilia with Factor VIII inhibitors late last year. Participants in the study were previously treated with episodic or prophylactic bypassing agents. The protocol recommends avoiding the use of aPCC whenever possible and only administering approved bypassing agents at low doses.